PROJECT SUMMARY/ABSTRACT Aggression is a highly complex, adaptive set of behaviors that has evolved to allow individuals to compete for limited resources (e.g., food, mates). Excessive or inappropriate aggressive behavior and violence, however, have become problematic in modern societies. Inappropriate aggression is associated with many neurological and psychiatric disorders. Indeed, untreated mental illness is a significant contributor to violence against self or others, and current treatments are largely ineffective. To find better treatments for serious mental illness and its relation to violence we must develop a comprehensive understanding of the neurobiological, physiological and neuroendocrine contributors to aggressive behavior. This knowledge is relevant to the NIH?s mission in that it will potentially provide novel targets for intervention for psychiatric disease. This grant proposes to use an integrative approach, drawing upon environmental biology, neuroendocrinology, pharmacology and molecular neuroscience to understand how the steroid hormone, dehydroepiandrosterone (DHEA) contributes to increased aggressive behavior in males and females. Our preliminary data support our hypothesis of a ?seasonal switch? from gonadal to adrenal regulation of aggression, a novel alternative endocrine mechanism regulating aggressive behaviors. Siberian hamsters are an ideal model to address novel non-gonadal mechanisms of aggression because they display high levels of aggression that occur independent of reproduction, allowing the relationship between gonadal steroids and aggression to be uncoupled. Likewise, in humans, there is equivocal empirical evidence for a strong direct relationship between high testosterone and aggression. Thus, the similarities between hamster and human adrenals make hamsters an ideal model system to experimentally test the link between DHEA and human aggression. By employing pharmacological and molecular genetic approaches we will test the hypothesis that melatonin acts directly on the adrenals to regulate DHEA synthesis and ultimately aggressive behavior (Specific Aim 1). We also test the hypothesis that DHEA is the key regulator of short-day and melatonin-induced aggression by applying pharmacological methods to block DHEA synthesis and its conversion to active metabolites (testosterone and 17-? estradiol) (Specific Aim 2). Uncovering the precise role of adrenal steroids (e.g., DHEA) in the regulation of aggressive behavior is vital to the development of a comprehensive approach to the treatment of inappropriate human aggression. More broadly, such studies will provide a foundation for understanding how variations in steroid hormones may interact with mental illness and contribute to aggressive behavior.